Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
Thorac Cancer. 2022 Aug;13(16):2318-2330. doi: 10.1111/1759-7714.14564. Epub 2022 Jul 5.
Malignant pleural mesothelioma (MPM) is one of the most aggressive tumors with few effective treatments worldwide. It has been suggested that alternative splicing at the transcriptome level plays an indispensable role in MPM.
We analyzed the splicing profile of 84 MPM patients from the TCGA cohort by using seven typical splicing types. We classified MPM patients based on their splicing status and conducted a comprehensive analysis of the correlation between the splicing classification and clinical characteristics, genetic variation, pathway changes, immune heterogeneity, and potential therapeutic targets.
The expression of the alternative splicing regulator SRPK1 is significantly higher in MPM tissues than in normal tissues, and correlates with poor survival. SRPK1 deficiency promotes MPM cell apoptosis and inhibits cell migration in vitro. We divided the MPM patients into four clusters based on their splicing profile and identified two clusters associated with the shortest (cluster 3) and longest (cluster 4) survival time. We present the different gene signatures of each cluster that are related to survival and splicing. Comprehensive analysis of data from the GDSC and TCGA databases revealed that cluster 3 MPM patients could respond well to the small-molecule inhibitor CHIR-99021, a small-molecule inhibitor of GSK-3.
We performed unsupervised clustering of alternative splicing data from 84 MPM patients from the TCGA database and identified a cluster associated with the worst prognosis that was sensitive to a GSK-3 inhibitor.
恶性胸膜间皮瘤（MPM）是世界范围内为数不多的几种有效治疗方法的侵袭性肿瘤之一。有研究表明，转录组水平的可变剪接在 MPM 中起着不可或缺的作用。
我们通过七种典型的剪接类型分析了来自 TCGA 队列的 84 名 MPM 患者的剪接谱。我们根据患者的剪接状态对 MPM 患者进行分类，并对剪接分类与临床特征、遗传变异、通路变化、免疫异质性和潜在治疗靶点之间的相关性进行综合分析。
在 MPM 组织中，剪接调节因子 SRPK1 的表达明显高于正常组织，且与生存不良相关。SRPK1 缺陷促进 MPM 细胞凋亡，抑制细胞迁移。我们根据剪接谱将 MPM 患者分为四个亚群，并确定了与最短（第 3 组）和最长（第 4 组）生存时间相关的两个亚群。我们展示了每个亚群与生存和剪接相关的不同基因特征。对 GDSC 和 TCGA 数据库数据的综合分析表明，第 3 组 MPM 患者对 GSK-3 小分子抑制剂 CHIR-99021 反应良好。
我们对来自 TCGA 数据库的 84 名 MPM 患者的可变剪接数据进行了无监督聚类，确定了一个与预后最差相关的亚群，该亚群对 GSK-3 抑制剂敏感。
